DOCSLIB.ORG

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’S Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’S Disease bioRxiv preprint doi: https://doi.org/10.1101/833988; this version posted November 7, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease How-Wing Leung, Gabriel Wei Quan Foo, Antonius M.J. VanDongen Program for Neuroscience and Behavioural Disorders, Duke-NUS Medical School, Singapore 169857 Correspondence: [email protected] ABSTRACT The immediate-early gene Arc is a master regulator of synaptic function and a critical determinant of memory consol- idation. Arc protein is localized to excitatory synapses, where it controls AMPA receptor endocytosis, and to the nucleus, where it associates with Tip60, a subunit of a chromatin modifying complex. Here we show that Arc interacts with dynamic chromatin loops and associates with histone markers for active enhancers and transcription in cultured hip- pocampal neurons. When Arc induction by pharmacological network activation was prevented using a short hairpin RNA, the expression profile was altered for over 1900 genes. Many gene families were affected by the absence of Arc, most notably those associated with synaptic function, neuronal plasticity, intrinsic excitability (channels, receptors, transporters), and signaling pathways (transcription factors/regulators). Interestingly, about 100 genes whose activity- dependent expression level depends on Arc are associated with the pathophysiology of Alzheimer’s disease, suggesting a critical role for Arc in the development of neurodegenerative disorders. When endogenous Arc expression was in- duced in a non-neuronal cell line (HEK293T), the transcription of many neuronal genes was increased, suggesting Arc can control expression in the absence of activated signaling pathways. Taken together, these data establish Arc as a master regulator of neuronal activity-dependent gene expression and a significant factor underlying the pathophysiol- ogy Alzheimer’s disease. with the acetylation status of one of Tip60’s substrate: lysine INTRODUCTION 12 of histone 4 (H4K12)25, a memory-associated histone mark The neuronal immediate-early gene Arc1,2 plays a critical role which declines with age29. These newly discovered nuclear in memory consolidation3-6. Arc expression is rapidly and tran- functions may point to an epigenetic role for Arc in memory siently induced by novel behavioural and sensory experiences7- consolidation. We have therefore investigated Arc’s interac- 11, while its mRNA is enriched in dendrites and targeted to re- tion with chromatin and its association with histone marks in cently activated synapses, where it is locally translated12,13. Arc cultured hippocampal and cortical neurons. Fluorescent mi- protein resides in excitatory synapses, where it controls AMPA croscopy experiments demonstrated a highly dynamic interac- receptor endocytosis14, allowing it to act as a master regulator tion between chromatin and Arc, as well as a tight association of synaptic function and plasticity15,16 that implements homeo- between Arc and histone marks for active enhancers and active static synaptic scaling at the neuronal network level17-19. While transcription. RNA-Sequencing (RNA-Seq) experiments in the synaptic role of Arc has been well documented, the ob- which activity-dependent Arc expression was prevented using served failure to convert early- to late-LTP in Arc knockout a short hairpin RNA showed that Arc regulates the transcrip- mice cannot be explained by an AMPA receptor endocytosis tion of over nineteen hundred genes controlling memory, cog- deficit4. This suggests that Arc may have additional functions. nition, synaptic function, neuronal plasticity, intrinsic excita- Interestingly, Arc protein can also be localized in the nucleus, bility and intracellular signaling. Interestingly, Arc also con- where it binds to a beta-spectrin IV isoform and associates with trols the expression of susceptibility genes for Alzheimer’s dis- PML bodies20-22, sites of epigenetic regulation of gene tran- ease, as well as many genes implicated in the pathophysiology scription23. Nuclear Arc has been reported to regulate tran- of this disorder. A Gene Ontology (GO) analysis identified scription of the GluA1 AMPA receptor24. Recently, another downstream signaling pathways and diseases associated with nuclear function for Arc has been demonstrated: Arc interacts the observed changes in mRNA levels, while an Ingenuity with the histone-acetyltransferase Tip6025, a subunit of a chro- Pathway Analysis (IPA) revealed upstream regulators pre- matin modifying complex26-28. Arc expression level correlates dicted by the change in gene expression profile caused by Arc Page 1 of 44 bioRxiv preprint doi: https://doi.org/10.1101/833988; this version posted November 7, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Leung et al 2019 knockdown. Finally, we induced expression of Arc in human phenylindole (DAPI). Whereas chromatin in Arc-negative embryonic kidney 293T (HEK-293T) cells, using CRISPR- neurons is relatively homogenous, the nuclei of Arc-positive Cas9, which resulted in the increased transcription of many neurons contain many bright puncta, representing neuronal genes. Taken together, our data demonstrate that Arc chromocenters with densely packed chromatin, in which genes controls neuronal activity-dependent expression of many are likely silenced (Fig. 2A and 2B). The puncta are genes underlying higher brain functions and may be involved interpersed with domains of highly open chromatin, which is in the development of Alzheimer’s disease (AD) and other more supportive of efficient gene transcription. The number of neurodegenerative disorders. puncta increased from 11.1±0.8 puncta in Arc-negative nuclei to 15.9±0.8 puncta in Arc-positive nuclei (Fig. 2C). However, the mean area of the puncta was not significantly different RESULTS between Arc-positive and Arc-negative neurons (Fig. 2D). Arc is a neuronal activity-dependent immediate-early gene1,2, Arc associates with dynamic chromatin. The interaction be- whose expression is induced by exposure to a novel tween Arc and chromatin was studied in more detail using environment or a new sensory experience7,8,11. Knockdown of time-lapse fluorescence microscopy of hippocampal neurons Arc expression abrogates long-term memory without affecting expressing Arc and histone 2B (H2B) tagged with YFP and short-term memory, indicating a critical role for Arc in mCherry, respectively (Fig. 3). Arc was induced in 18 days in memory consolidation3-6. Arc protein localizes to dendritic vitro (DIV) hippocampal neurons by a 4-hour treatment with spines, where it regulates AMPA receptor endocytosis14, and 4BF. The time-lapse movies of Arc-eYFP and H2B-mCherry to the nucleus20,24,30,31, where its function is less understood. In revealed a highly dynamic chromatin that constantly reorgan- this study we have used cultured hippocampal and cortical izes on a time scale of seconds (Movie 1). Arc is concentrated neurons to study the role of Arc in the nucleus. Arc expression in small puncta to which the chromatin can be seen to reach can be induced by increasing network activity in neuronal out with finger-like structures, which likely represent the dy- cultures, using a combination of 4-aminopyridine (4AP), namic chromatin loops described by others53-55. bicuculline and forskolin (4BF), a form of pharmacological long-term potentiation (LTP)21,22,32,33. Figure 1 shows that this Arc associates with a marker of active enhancers. Because form of network activation strongly induces the expression of Arc was shown to associate with the Tip60 substrate Arc in a subset of neurons. In this in vitro paradigm, Arc H4K12Ac25, we have examined interactions of Arc with other localizes predominantly to the nucleus four hours after histone modifications, by comparing Arc-positive and -nega- network activity-dependent induction of its expression. tive neurons following pharmacological network activation. 56 Memory consolidation requires de novo gene expression34,35, The ‘histone code’ is complex and still incompletely under- which is induced by activation of signaling cascades that stood. We have therefore focused on histone modifications originate in the synaptic connections potentiated during whose function is best studied. In our survey we have found learning36-40. This synapse-to-nucleus signaling results in post- several histone modifications for which there was a difference translational modifications of chromatin, including in nuclear organization between Arc positive and negative neu- acetylation, methylation, phosphorylation, and sumoylation of rons, including H3K9Ac, H3K4me3, and H3K14Ac (data not histones and methylation of DNA41,42. Chromatin modification shown). Figure 4 illustrates the close association between Arc 57,58 alters its nanostructure, which controls accessibility of gene and H3K27Ac, which marks active enhancers . Arc and promoters to the transcription machinery43,44. These synaptic H3K27Ac form two separate lattice-like structures that are activity-induced epigenetic processes can alter gene closely inter-connected and, in some
Load more

Recommended publications
  • KAT5 Promotes Invasion and Metastasis Through C-MYC Stabilization in ATC
    26 1 Endocrine-Related X Wei, S Cai et al. KAT5 in anaplastic thyroid 26:1 141–151 Cancer carcinoma RESEARCH KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC Xi Wei1,*, Shang Cai2,3,*, Rebecca J Boohaker2, Joshua Fried2, Ying Li4, Linfei Hu5, Yi Pan5, Ruifen Cheng5, Sheng Zhang1, Ye Tian3, Ming Gao5 and Bo Xu2,6 1Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 2Department of Oncology, Southern Research Institute and Cancer Cell Biology Program, the University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, USA 3Department of Radiotherapy and Oncology, the Second Affiliated Hospital ofoochow S University, Suzhou, China 4The Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 5Department of Thyroid Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 6Department of Molecular Radiation Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Correspondence should be addressed to B Xu or M Gao: [email protected] or [email protected] or [email protected] *(X Wei and S Cai contributed equally to this work) Abstract Anaplastic thyroid cancer (ATC) is an aggressive cancer with poor clinical prognosis. Key Words However, mechanisms driving ATC aggressiveness is not well known.
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • KAT5 Acetylates Cgas to Promote Innate Immune Response to DNA Virus
    KAT5 acetylates cGAS to promote innate immune response to DNA virus Ze-Min Songa, Heng Lina, Xue-Mei Yia, Wei Guoa, Ming-Ming Hua, and Hong-Bing Shua,1 aDepartment of Infectious Diseases, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, 430071 Wuhan, China Edited by Adolfo Garcia-Sastre, Icahn School of Medicine at Mount Sinai, New York, NY, and approved July 30, 2020 (received for review December 19, 2019) The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic mi- suppress its enzymatic activity (15). It has also been shown that crobial or self DNA to initiate a MITA/STING-dependent innate im- the NUD of cGAS is critically involved in its optimal DNA- mune response. cGAS is regulated by various posttranslational binding (16), phase-separation (7), and subcellular locations modifications at its C-terminal catalytic domain. Whether and (17). However, whether and how the NUD of cGAS is regulated how its N-terminal unstructured domain is regulated by posttrans- remains unknown. lational modifications remain unknown. We identified the acetyl- The lysine acetyltransferase 5 (KAT5) is a catalytic subunit of transferase KAT5 as a positive regulator of cGAS-mediated innate the highly conserved NuA4 acetyltransferase complex, which immune signaling. Overexpression of KAT5 potentiated viral- plays critical roles in DNA damage repair, p53-mediated apo- DNA–triggered transcription of downstream antiviral genes, whereas ptosis, HIV-1 transcription, and autophagy (18–21). Although a KAT5 deficiency had the opposite effects. Mice with inactivated KAT5 has been investigated mostly as a transcriptional regula- Kat5 exhibited lower levels of serum cytokines in response to DNA tor, there is increasing evidence that KAT5 also acts as a key virus infection, higher viral titers in the brains, and more susceptibility regulator in signal transduction pathways by targeting nonhis- to DNA-virus–induced death.
    [Show full text]
  • Atrazine and Cell Death Symbol Synonym(S)
    Supplementary Table S1: Atrazine and Cell Death Symbol Synonym(s) Entrez Gene Name Location Family AR AIS, Andr, androgen receptor androgen receptor Nucleus ligand- dependent nuclear receptor atrazine 1,3,5-triazine-2,4-diamine Other chemical toxicant beta-estradiol (8R,9S,13S,14S,17S)-13-methyl- Other chemical - 6,7,8,9,11,12,14,15,16,17- endogenous decahydrocyclopenta[a]phenanthrene- mammalian 3,17-diol CGB (includes beta HCG5, CGB3, CGB5, CGB7, chorionic gonadotropin, beta Extracellular other others) CGB8, chorionic gonadotropin polypeptide Space CLEC11A AW457320, C-type lectin domain C-type lectin domain family 11, Extracellular growth factor family 11, member A, STEM CELL member A Space GROWTH FACTOR CYP11A1 CHOLESTEROL SIDE-CHAIN cytochrome P450, family 11, Cytoplasm enzyme CLEAVAGE ENZYME subfamily A, polypeptide 1 CYP19A1 Ar, ArKO, ARO, ARO1, Aromatase cytochrome P450, family 19, Cytoplasm enzyme subfamily A, polypeptide 1 ESR1 AA420328, Alpha estrogen receptor,(α) estrogen receptor 1 Nucleus ligand- dependent nuclear receptor estrogen C18 steroids, oestrogen Other chemical drug estrogen receptor ER, ESR, ESR1/2, esr1/esr2 Nucleus group estrone (8R,9S,13S,14S)-3-hydroxy-13-methyl- Other chemical - 7,8,9,11,12,14,15,16-octahydro-6H- endogenous cyclopenta[a]phenanthren-17-one mammalian G6PD BOS 25472, G28A, G6PD1, G6PDX, glucose-6-phosphate Cytoplasm enzyme Glucose-6-P Dehydrogenase dehydrogenase GATA4 ASD2, GATA binding protein 4, GATA binding protein 4 Nucleus transcription TACHD, TOF, VSD1 regulator GHRHR growth hormone releasing
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • Sponges Are Highly Resistant to Radiation Exposure and Cancer
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.17.435910; this version posted March 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Sponges are highly resistant to radiation exposure and cancer Angelo Fortunato1,2,3†, Jake Taylor1,2,3, Jonathan Scirone1,2,3, Athena Aktipis1,4* and Carlo C. Maley1,2,3* 1. Arizona Cancer Evolution Center, Arizona State University, 1001 S. McAllister Ave., Tempe, AZ, 85287, USA. 2. Biodesign Center for Biocomputing, Security and Society, Arizona State University, 727 E. Tyler St.,Tempe, AZ 85281, USA. 3. School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, AZ 85287, USA. 4. Department of Psychology, Arizona State University, Tempe, AZ, USA. † Corresponding author * co-senior authors bioRxiv preprint doi: https://doi.org/10.1101/2021.03.17.435910; this version posted March 19, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract There are no reports of cancer in sponges, despite them having somatic cell turnover, long lifespans and no specialized adaptive immune cells. In order to investigate whether sponges are cancer resistant, we exposed a species of sponge, Tethya wilhelma, to X-rays. We found that T. wilhelma can withstand 600 Gy of X-ray radiation. That is approximately 100 times the lethal dose for humans. A single high dose of X-rays did not induce cancer in sponges, providing the first experimental evidence of cancer resistance in the phylum, Porifera.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Murine Neonatal Ketogenesis Preserves Mitochondrial Energetics by Preventing Protein Hyperacetylation
    ARTICLES https://doi.org/10.1038/s42255-021-00342-6 Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation Yuichiro Arima 1,2,13 ✉ , Yoshiko Nakagawa3,13, Toru Takeo 3,13, Toshifumi Ishida 1, Toshihiro Yamada1, Shinjiro Hino4, Mitsuyoshi Nakao4, Sanshiro Hanada 2, Terumasa Umemoto 2, Toshio Suda2, Tetsushi Sakuma 5, Takashi Yamamoto5, Takehisa Watanabe6, Katsuya Nagaoka6, Yasuhito Tanaka6, Yumiko K. Kawamura7,8, Kazuo Tonami7, Hiroki Kurihara7, Yoshifumi Sato9, Kazuya Yamagata9,10, Taishi Nakamura 1,11, Satoshi Araki1, Eiichiro Yamamoto1, Yasuhiro Izumiya1,12, Kenji Sakamoto1, Koichi Kaikita1, Kenichi Matsushita 1, Koichi Nishiyama2, Naomi Nakagata3 and Kenichi Tsujita1,10 Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear. Here, we show that neonatal ketogen- esis plays a protective role in mitochondrial function. We generated a mouse model of insufficient ketogenesis by disrupting the rate-limiting hydroxymethylglutaryl-CoA synthase 2 enzyme gene (Hmgcs2). Hmgcs2 knockout (KO) neonates develop microvesicular steatosis within a few days of birth. Electron microscopic analysis and metabolite profiling indicate a restricted energy production capacity and accumulation of acetyl-CoA in Hmgcs2 KO mice. Furthermore,
    [Show full text]
  • The Circadian Transcriptome of Marine Fish (Sparus Aurata) Larvae Reveals
    www.nature.com/scientificreports OPEN The circadian transcriptome of marine fsh (Sparus aurata) larvae reveals highly synchronized Received: 24 May 2017 Accepted: 22 September 2017 biological processes at the whole Published: xx xx xxxx organism level M. Yúfera1, E. Perera2, J. A. Mata-Sotres1,3, J. Calduch-Giner2, G. Martínez-Rodríguez1 & J. Pérez-Sánchez2 The regulation of circadian gene expression remains largely unknown in farmed fsh larvae. In this study, a high-density oligonucleotide microarray was used to examine the daily expression of 13,939 unique genes in whole gilthead sea bream (Sparus aurata) larvae with fast growth potentiality. Up to 2,229 genes were diferentially expressed, and the frst two components of Principal Component Analysis explained more than 81% of the total variance. Clustering analysis of diferentially expressed genes identifed 4 major clusters that were triggered sequentially, with a maximum expression at 0 h, 3 h, 9–15 h and 18-21 h zeitgeber time. Various core clock genes (per1, per2, per3, bmal1, cry1, cry2, clock) were identifed in clusters 1–3, and their expression was signifcantly correlated with several genes in each cluster. Functional analysis revealed a daily consecutive activation of canonical pathways related to phototransduction, intermediary metabolism, development, chromatin remodeling, and cell cycle regulation. This daily transcriptome of whole larvae resembles a cell cycle (G1/S, G2/M, and M/ G1 transitions) in synchronization with multicellular processes, such as neuromuscular development. This study supports that the actively feeding fsh larval transcriptome is temporally organized in a 24-h cycle, likely for maximizing growth and development. Te evolution of many organisms has been driven by circadian rhythms to adapt to periodic events in their exter- nal environments.
    [Show full text]
  • TIP55, a Splice Isoform of the KAT5 Acetyltransferase, Is
    www.nature.com/scientificreports OPEN TIP55, a splice isoform of the KAT5 acetyltransferase, is essential for developmental gene regulation and Received: 27 March 2018 Accepted: 24 September 2018 organogenesis Published: xx xx xxxx Diwash Acharya1, Bernadette Nera1, Zachary J. Milstone2,3, Lauren Bourke 2,3, Yeonsoo Yoon4, Jaime A. Rivera-Pérez4, Chinmay M. Trivedi 1,2,3 & Thomas G. Fazzio1 Regulation of chromatin structure is critical for cell type-specifc gene expression. Many chromatin regulatory complexes exist in several diferent forms, due to alternative splicing and diferential incorporation of accessory subunits. However, in vivo studies often utilize mutations that eliminate multiple forms of complexes, preventing assessment of the specifc roles of each. Here we examined the developmental roles of the TIP55 isoform of the KAT5 histone acetyltransferase. In contrast to the pre-implantation lethal phenotype of mice lacking all four Kat5 transcripts, mice specifcally defcient for Tip55 die around embryonic day 11.5 (E11.5). Prior to developmental arrest, defects in heart and neural tube were evident in Tip55 mutant embryos. Specifcation of cardiac and neural cell fates appeared normal in Tip55 mutants. However, cell division and survival were impaired in heart and neural tube, respectively, revealing a role for TIP55 in cellular proliferation. Consistent with these fndings, transcriptome profling revealed perturbations in genes that function in multiple cell types and developmental pathways. These fndings show that Tip55 is dispensable for the pre- and early post-implantation roles of Kat5, but is essential during organogenesis. Our results raise the possibility that isoform-specifc functions of other chromatin regulatory proteins may play important roles in development.
    [Show full text]
  • Peroxisomal Β-Oxidation Regulates Histone Acetylation and DNA Methylation in Arabidopsis
    Peroxisomal β-oxidation regulates histone acetylation and DNA methylation in Arabidopsis Lishuan Wanga,1, Chunlei Wangb,1, Xinye Liuc, Jinkui Chenga, Shaofang Lia, Jian-Kang Zhud,e,2, and Zhizhong Gonga,2 aState Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, 100193 Beijing, China; bCollege of Horticulture, Gansu Agricultural University, 730070 Lanzhou, China; cMinistry of Education Key Laboratory of Molecular and Cellular Biology, College of Life Sciences, Hebei Normal University, 050024 Shijiazhuang, China; dShanghai Center for Plant Stress Biology, National Key Laboratory of Plant Molecular Genetics, Center of Excellence in Molecular Plant Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 200032 Shanghai, China; and eDepartment of Horticulture and Landscape Architecture, Purdue University, West Lafayette, IN 47907 Contributed by Jian-Kang Zhu, April 4, 2019 (sent for review March 12, 2019; reviewed by Bao Liu and Jim Peacock) Epigenetic markers, such as histone acetylation and DNA methylation, DNA methylation is a conserved epigenetic marker important determine chromatin organization. In eukaryotic cells, metabolites in genome organization, gene expression, genomic imprinting, from organelles or the cytosol affect epigenetic modifications. How- paramutation, and X chromosome inactivation in organisms (3, ever, the relationships between metabolites and epigenetic modifica- 11–13). DNA methylation patterns are coordinately determined tions are not well understood in plants. We found that peroxisomal by methylation and demethylation reactions in plants and ani- acyl-CoA oxidase 4 (ACX4), an enzyme in the fatty acid β-oxidation mals (13, 14). The active removal of 5mC in Arabidopsis is car- pathway, is required for suppressing the silencing of some endoge- ried out by a subfamily of bifunctional DNA glycosylases/lyases nous loci, as well as Pro35S:NPTII in the ProRD29A:LUC/C24 transgenic represented by REPRESSOR OF SILENCING 1 (ROS1) and line.
    [Show full text]
  • The Wild-Type and Gain-Of-Function Mutant P53 Enhance P300 Autoacetylation Through Conformational Switching
    bioRxiv preprint doi: https://doi.org/10.1101/194704; this version posted May 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The Wild-type and Gain-of-function Mutant p53 Enhance p300 Autoacetylation through Conformational Switching Stephanie Kaypee1,4, Raka Ghosh2,4, Smitha Asoka Sahadevan1, Shilpa Patil1,5, Manidip Shasmal2,6, Piya Ghosh2, Neeladri Roy2,7, Jayati Sengupta3,*, Siddhartha Roy2,*, and Tapas K. Kundu1,* 1Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, Karnataka, India; 2Department of Biophysics, Bose Institute, Kolkata, India; 3Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India. * To whom correspondence should be addressed: [email protected], [email protected], [email protected] 4 These authors contributed equally to the paper as first authors. 5 Current Address: Department of Gastroenterology and GI oncology, University Medical Center, Goettingen, Germany 6 Current Address: Government General Degree College, Keshiary West Bengal Education Service, West Bengal, India 7 Current Address: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA 1 bioRxiv preprint doi: https://doi.org/10.1101/194704; this version posted May 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT The transcriptional coactivator p300 is essential for p53 transactivation, although its precise mechanism remains unclear. We report that, p53 allosterically activates the acetyltransferase activity of p300 through the enhancement of p300 autoacetylation.
    [Show full text]